The present invention relates to novel, substituted hydroxyindoles processes for their preparation, pharmaceutical preparations containing these compounds, and a method for the use of these compounds which are phosphodiesterase 4 inhibitors, as active compounds for the treatment of disorders which can be affected by inhibition of phosphodiesterase 4 activity in immunocompetent cells (e.g. macrophages and lymphocytes).
The activation of cell membrane receptors by transmitters leads to the activation of the second messenger system. Adenylate cyclase synthesizes active cyclic AMP (cAMP) or cyclic GMP (cGMP) from AMP and GMP. These lead, for example, to relaxation in smooth muscle cells or to inhibition of mediator release or synthesis in inflammatory cells. The breakdown of the second messenger cAMP and cGMP is carried out by the phosphodiesterases (PDE). To date, 7 families of PDE enzymes (PDE1-7) are known, which differ by their substrate specificity (cAMP, cGMP or both) and the dependence on other substrates (e.g. calmodulin). These isoenzymes have different functions in the body and are prominent to different extents in the individual cell types (Beave J A, Conti M and Heaslip R J, Multiple cyclic nucleotide phosphodiesterases, Mol. Pharmacol. 1994, 46: 399-405; Hall I P, Isoenzyme selective phosphodiesterase inhibitors; potential clinical uses, Br. J. clin. Pharmacol. 1993, 35: 1-7). As a result of inhibition of the various PDE isoenzyme types, there is an accumulation of cAMP or cGMP in the cells, which can be therapeutically utilized (Torphy T J, Livi G P, Christensen S B, Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).
In the cells important for allergic inflammation (lymphocytes, mast cells, eosinophilic granulocytes, macrophages), the prevailing PDE isoenzyme is of type 4 (Torphy, J T. and Undem, B. J., Phosphodiesterase inhibitors: new opportunities for the treatment of asthma, Thorax 1991, 46: 512-523). The inhibition of PDE 4 by suitable inhibitors is therefore considered as an important starting point for the therapy of a large number of allergically induced disorders (Schudt Ch, Dent G, Rabe K, Phosphodiesterase Inhibitors, Academic Press London 1996).
An important property of phosphodiesterase 4 inhibitors is the inhibition of the release of tumour necrosis factor xcex1 (TNFxcex1) from inflammatory cells. TNFxcex1 is an important pro-inflammatory cytokine, which affects a large number of biological processes. TNFxcex1 is released, for example, from activated macrophages, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. It has a self-activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, as a result of which various tissue-destroying mediators are released. In monocytes, macrophages and T lymphocytes, TNFxcex1 brings about the increased production of further pro-inflammatory cytokines such as GM-CSF (granulocyte-macrophage colony-stimulating factor) or interleukin-8. TNFxcex1 plays a central part due to its inflammation-promoting and catabolic action in a large number of disorders, such as inflammation of the airways, inflammation of the joints, endotoxic shock, tissue rejection, AIDS and numerous other immunological disorders. Inhibitors of phosphodiesterase 4 are thus also suitable for the therapy of disorders of this type which are associated with TNFxcex1.
Chronic obstructive pulmonary diseases (COPD) are widespread in the population and also have great economic importance. Thus COPD diseases cause about 10-15% of all illness costs in the developed countries and about 25% of all cases of death in the USA are to be attributed to this cause (Norman P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998), however the patients at the time of death are usually over 55 years old (Nolte D.: Chronische Bronchitis-eine Volkskrankheit multifaktorieller Genese. Atemw.-Lungenkrkh. [Chronic bronchitisxe2x80x94a widespread disease of multifactorial origin]. 20 (5), 260-267, 1994). The WHO estimates that COPD will be the third most frequent cause of death within the next 20 years.
The syndrome of chronic obstructive lung diseases (COPD) summarizes various syndromes of chronic bronchitis with the symptoms coughing and expectoration and progressive and irreversible impairment of lung function (exhalation is particularly affected). The course of the disease is episodic and often complicated by bacterial infections (Rennard S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998). In the course of the disease, the lung function continuously decreases, the lungs become increasingly emphysematous and the respiratory distress of the patients is obvious. This disease clearly adversely affects the quality of life of the patients (dyspnoea, low exercise tolerance) and significantly reduces their life expectancy. The main risk factor besides environmental factors is smoking (Kummer F.: Asthma und COPD. Atemw.-Lungenkrkh. 20 (5), 299-302, 1994; Rennard S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998) and therefore men are clearly more often affected than women. As a result of the change in living habits and the increase in the number of smokers, this picture, however, will change in future.
The current therapy aims only at the alleviation of the symptoms, without causally intervening in the progression of the disease. The use of long-acting Beta2 agonists (e.g. salmeterol) possibly in combination with muscarinergic antagonists (e.g. ipratropium) improves the lung function by bronchodilatation and is employed routinely (Norman P.: COPD: New developments and therapeutic opportunities, Drugs News Perspect. 11 (7), 431-437, 1998). A large part in the COPD episodes is played by bacterial infections, which have to be treated with antibiotics (Wilson R.: The role of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman R. F.: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S-255S, 1998). The therapy of this disease is unsatisfactory as yet, particularly with respect to the continuous decrease in lung function. New therapeutic approaches which affect inflammatory mediators, proteases or adhesion molecules could be very promising (Barnes P. J.: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).
Independently of the bacterial infections complicating the disease, a chronic inflammation which is dominated by neutrophilic granulocytes is found in the bronchi. The mediators and enzymes released by neutrophilic granulocytes, inter alia, have been held responsible for the structural changes observed in the airways (emphysema). The inhibition of the activity of the neutrophilic granulocytes is thus a rational approach to prevent or to slow down progression of COPD (impairment of lung function parameters). An important stimulus for the activation of the granulocytes is the pro-inflammatory cytokine TNFxcex1 (tumour necrosis factor). Thus it is known that TNFxcex1 stimulates the formation of oxygen radicals by neutrophilic granulocytes (Jersmann, H. P. A.; Rathjen, D. A. and Ferrante A.: Enhancement of LPS-induced neutrophil oxygen radical production by TNFxcex1, Infection and Immunity, 4, 1744-1747, 1998). PDE4 inhibitors can very effectively inhibit the release of TNFxcex1 from a large number of cells and thus suppress the activity of the neutrophilic granulocytes. The non-specific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen radicals and the phagocytosability of neutrophilic granulocytes (Wenisch, C.; Zedtwitz-Liebenstein, K.; Parschalk, B. and Graninger W.: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug. Invest., 13(2):99-104, 1997).
Various PDE 4 inhibitors are already known. As a matter of priority, these are xanthine derivatives, rolipram analogues or nitraquazone derivatives (general survey in: Karlsson J-A, Aldos D, Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003). Until now, it was not possible to use any of these compounds clinically. It had to be established that the known PDE 4 inhibitors also have various side-effects such as nausea and emesis, which it was not possible to suppress adequately until now. The discovery of new PDE 4 inhibitors with better therapeutic breadth is therefore necessary.
Although indoles have been playing an important part for many years in the development of new active compounds for various indications, until now hydroxyindoles were completely unknown as inhibitors of PDE 4.
The invention relates to substituted hydroxyindoles of the Formula 
and their pharmaceutically acceptable salts, wherein R1, R5 are independently of each other
(i) a [C1-12 alkyl, straight chain or branched-chain, optionally mono- or polysubstituted by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl) (C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl,
xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO3H, xe2x80x94SO2R6, xe2x80x94OSO2C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94(CS)R6, xe2x80x94COOH, xe2x80x94(CO)R6, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 hetero atoms, which are suitable N, O and S, where the C6-4 aryl groups and the included carbocyclic and heterocyclic substituents can optionally be mono- or polysubstituted by R4.
(ii) xe2x80x94C2-12 alkenyl, mono- or polyunsaturated, straight-chain or branched-chain optionally mono- or polysubstituted by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl) (C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO3H, xe2x80x94SO2R6, xe2x80x94OSO2C1-6 alkyl, xe2x80x94OSO2C6-14 aryl, xe2x80x94(CS)R6, xe2x80x94COOH, xe2x80x94(CO)R6, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S, where the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents for their part can optionally be mono- or polysubstituted by R4,
(iii) mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, optionally mono- or polysubstituted by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl)(C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO3H, xe2x80x94SO2R6, OSO2C1-6 alkyl, xe2x80x94OSO2C6-14 aryl, xe2x80x94(CS)R6, xe2x80x94COOH, xe2x80x94(CO)R6, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S, where the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents can optionally be mono- or polysubstituted by R4,
(iv) mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S, optionally mono- or polysubstituted by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl)(C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO3H, xe2x80x94SO2R6, xe2x80x94OSO2C1-6 alkyl, xe2x80x94OSO2C6-14 aryl, xe2x80x94(CS)R6, xe2x80x94COOH, xe2x80x94(CO)R6, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S, where the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents for their part can be optionally mono- or polysubstituted by R4, -carbo- or heterocyclic saturated or mono- or polyunsaturated spirocycles having from 3 to 10 ring members, where heterocyclic systems contains from 1 to 6 heteroatoms, which are suitably N, O and S, optionally mono- or polysubstituted by xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl) (C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C6-14 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO3H, xe2x80x94SO2R6, xe2x80x94OSO2C1-6 alkyl, xe2x80x94OSO2C6-14 aryl, xe2x80x94(CS)R6, xe2x80x94COOH, xe2x80x94(CO)R6, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S, where the C6-14 aryl groups and the included carbocyclic and heterocyclic substituents can optionally be mono- or polysubstituted by R4,
R2, R3 are hydrogen or xe2x80x94OH, where at least one of the two substituents must be xe2x80x94OH;
R4 is xe2x80x94H, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl)(C6-14 aryl), xe2x80x94NHCOR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOH, xe2x80x94(CO)R6, xe2x80x94(CS)R6, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94O(CO)R6, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94SOR6, xe2x80x94SO2R6.
R6 is xe2x80x94H, xe2x80x94NH2, xe2x80x94NHC1-6 alkyl, xe2x80x94N(C1-6 alkyl)2, xe2x80x94NHC6-14 aryl, xe2x80x94N(C6-14 aryl)2, xe2x80x94N(C1-6 alkyl)(C6-14 aryl), xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94Oxe2x80x94C6-14 aryl, xe2x80x94Sxe2x80x94C1-6 alkyl, xe2x80x94Sxe2x80x94C6-14 aryl, xe2x80x94C1-12 alkyl, straight-chain or branched-chain, xe2x80x94C2-12 alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S;
A is either a bond, or xe2x80x94CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94(CHxe2x95x90CH)nxe2x80x94(CH2)Pxe2x80x94, xe2x80x94(CHOZ)mxe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Cxe2x95x90S)xe2x80x94, xe2x80x94(Cxe2x95x90Nxe2x80x94Z)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NZxe2x80x94, where m and p are cardinal numbers from 0 to 3 and n is a cardinal number from 0 to 2,
Z is H, or a C1-12 alkyl, straight-chain or branched-chain, C2-12 alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles having from 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having from 5 to 15 ring members and from 1 to 6 heteroatoms, which are suitably N, O and S;
B is either carbon or sulfur, or xe2x80x94(Sxe2x95x90O)xe2x80x94;
D is oxygen, sulfur, CH2 or Nxe2x80x94Z, where D can only be S or CH2 if B is carbon;
E is a bond, or (CH2)mxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Nxe2x80x94Z)xe2x80x94, where m and Z have the same meanings as above.
The most suitable compounds of Formula (1) include
N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide Na salt;
N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl])-5-hydroxyindol-3-yl]-2-hydroxyacetamide;
N-(pyridin-4-yl)-2-[1-2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-2-[1-(2,6-difluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-2-[1-(3-nitrobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide Na salt;
N-(3,5-dichloropyridin-4-yl)-2-(1-propyl-5-hydroxyindol-3-yl)-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-2-(1-isopropyl-5-hydroxyindol-3-yl)-2-oxoacetarmide;
N-(3,5-dichloropyridin-4-yl)-2-(1-cyclopentylmethyl-5-hydroxyindol-3-yl)-2-oxoacetamide;
N-(2,6-dichlorophenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]-2-oxoacetamide;
N-(2,6-dichloro-4-trifluoromethylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;
N-(2,6-dichloro-4-trifluoromethoxylphenyl)-2-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl)-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-2-[1-(4-fluorobenzyl)-6-hydroxyindol-3-yl]-2-oxoacetamide;
N-(3,5-dichloropyridin-4-yl)-5-hydroxy-1-(4-methoxybenzyl)indole-3-carboxamide.
The pharmaceutically acceptable salts are obtained in a customary manner by neutralization of the bases with inorganic or organic acids or by neutralization of the acids with inorganic or organic bases. Possible inorganic acids are, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, organic acids are, for example, carboxylic, sulfo or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid. Possible inorganic bases are, for example, sodium hydroxide solution, potassium hydroxide solution, ammonia, and possible organic bases are amines, suitably tertiary amines, such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, (-picoline, (-picoline, (-picoline, quinaldine or pyrimidine.
In addition, pharmaceutically acceptable salts of the compound of Formula (1) can be obtained by converting derivatives which have tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se by using quaternizing agents. Possible quaternizing agents are, for example, alkyl halides such as methyl iodide, ethyl bromide and n-propyl chloride, but also arylalkyl halides such as benzyl chloride or 2-phenylethyl bromide.
Furthermore, the invention of the compounds of Formula (1) which contain an asymmetric carbon atom relates to the D form, the L form and D,L mixtures and, in the case of a number of asymmetric carbon atoms, the diastereomeric forms. Those compounds of Formula (1) which contain asymmetric carbon atoms and as a rule are obtained as racemates can be separated into the optically active isomers in a manner known per se, for example using an optically active acid. However, it is also possible to employ an optically active starting substance from the start, a corresponding optically active or diastereomeric compound then being obtained as the final product.
The compounds of the present invention have therapeutically useful pharmacological properties as inhibitors of the release of TNFxcex1. These disorders include, for example, arthritides including arthritis and rheumatoid arthritis and other arthritic disorders such as rheumatoid spondylitis and osteoarthritis. Further possibilities of their application include the treatment of patients suffering from sepsis, septic shock, gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma and other chronic pulmonary disorders, bone resorption diseases or transplant rejection reactions or other autoimmune disorders, such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and chronic demyelinization.
Moreover, the compounds of the present invention can also be employed for the therapy of infections such as virus and parasite infections, for example, for the therapy of malaria, infection-related fever, infection-related myalgia, AIDS and cachexia.
The compounds according to the invention are inhibitors of phosphodiesterase 4 (PDE 4). Therefore, the compounds of Formula (1) and their salts, and pharmaceutical preparations which contain these compounds or their salts, can be used for the treatment of disorders in which inhibition of phosphodiesterase 4 is beneficial.
Thus the compounds according to the invention can be employed as bronchodilators and for asthma prophylaxis. Compounds of Formula (1) also inhibit of the accumulation and activity of eosinophils. Accordingly, the compounds according to the invention can also be employed in disorders in which eosinophils play a part. These disorders include, for example, inflammatory airway disorders such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammations mediated by eosinophils such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria, ulcerative colitis, Crohn s disease and proliferative skin disorders such as psoriasis or keratosis.
According to the present invention the compounds of Formula (1) and their salts can inhibit both the lipopolysaccharide (LPS)-induced release of TNFxcex1 in human blood in vitro, and the LPS-induced pulmonary neutrophilic infiltration in ferrets and domestic pigs in vivo. All the pharmacologically important properties that were found confirm that the compounds of Formula (1) and their salts as well as pharmaceutical preparations which contain these compounds or their salts can be used therapeutically for the treatment of chronic obstructive pulmonary diseases.
The compounds of the invention also have neuroprotective properties and can be used for the therapy of diseases in which neuroprotection is beneficial. Such disorders are, for example, senile dementia (Alzheimer""s disease), loss of memory, Parkinson""s disease, depression, stroke and intermittent claudication.
Further applications of the compounds of the invention include the prophylaxis and therapy of prostate diseases, such as, for example, benign prostate hyperplasia, pollakiuria, nycturia; and for the treatment of atony of the bladder and of colics caused by kidney stones.
Finally, the compounds according to the invention can also be used for the inhibition of the development of drug dependence on repeated use of analgesics, such as, for example, morphine, and for the reduction of the development of tolerance on repeated use of these analgesics.
An efficective amount of the compounds according to the invention or their salts is used for producing medicaments of the present invention, along with conventional pharmaceutical auxiliaries, carriers and additives.
The dose of the active compounds can vary depending on factors such as the route of administration, age and weight of the patient, nature and severity of the disorders to be treated and similar factors. Therefore, any reference herein to a pharmacologically effective amount of the compounds of the present invention refers to the aforementioned factors.
The daily dose can be given as an individual dose to be administered once or subdivided into two or more daily doses suitably from about 0.001 mg to about 100 mg each.
Possible forms of administration include oral, parenteral, intravenous, transdermal, topical, inhalational and intranasal preparations. For administration, possible customary pharmaceutical dosage forms include tablets, coated tablets, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrup, juices and drops.
Solid pharmaceutical forms can contain inert ingredients and carriers, such as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminium stearates, methylcellulose, talc, highly disperse salicylic acids, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatin, agarxe2x80x94agar or vegetable or animal fats and oils, solid high molecular weight polymers (such as polyethylene glycol); preparations suitable for oral administration can, if desired, contain additional flavorings and/or sweeteners.
Liquid pharmaceutical forms can be sterilized and/or optionally contain auxiliaries such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulation of the osmotic pressure or for buffering, and/or viscosity regulators.
Additives of this type include, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its nontoxic salts). For regulation of the viscosity, possible high molecular weight polymers are those such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin. Solid carriers include, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse salicylic acids, high molecular weight fatty acids (such as stearic acid), gelatin, agarxe2x80x94agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycol.
Oily suspensions for parenteral or topical application can include vegetable synthetic or semi-synthetic oils such as, for example, liquid C8-22 fatty acid esters, for example palmitic, lauric, tridecylic, margaric, stearic, arachidic, myristic, behenic, pentadecanoic, linoleic, elaidic, brassidic, erucic or oleic acid, which are esterified with mono- to C1-6 trihydric alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Fatty acid esters of this type are, for example, commercially available Miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters such as artificial duck preen gland fat, isopropyl cocoate, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters and others. Also suitable are silicone oils of differing viscosities or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as, for example, oleic acid. Furthermore, vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, groundnut oil or soya bean oil can be used.
Possible solvents, gel-forming agents and solubilizers are water or water-miscible solvents. Those suitable are, for example, alcohols such as, for example, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methylcellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone etc.
Film-forming agents which can be used are cellulose ethers which can dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches.
Mixed forms between gel- and film-forming agents are also possible. Those used here are especially ionic macromolecules, such as, for example, sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
Further formulation auxiliaries which can be employed include glycerol, paraffin of differing viscosities, triethanolamine, collagen, allantoin, novantisolic acid.
The use of surfactants, emulsifiers or wetting agents can also be necessary for formulation, such as, for example, of Na lauryl sulfate, fatty alcohol ether sulfates, di-Na N-lauryl-(-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenyl polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkyl polyglycol ether orthophosphoric acid monoethanolamine salts.
Stabilizers such as montmorillonites or colloidal salicylic acids for the stabilization of emulsions or for the prevention of the breakdown of the active substances, such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise optionally be required for the preparation of the desired formulations.
Preparations for parenteral administration can be present in separate dose unit forms such as, for example, ampoules or vials. Suitably, solutions of the active compound are used, most suitably aqueous solutions and especially isotonic solutions, and also suspensions. These injection forms can be made available as finished preparations or prepared only directly before administration by mixing the active compound, for example the lyophilizate, if appropriate with further solid carriers, with the desired solvent or suspending agent.
Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilizates, which are prepared before administration using the suitable solvent or suspending agent.
The production, dispensation and sealing of the preparations is carried out under the conventional antimicrobial and aseptic conditions.
The invention furthermore relates to processes for the preparation of the compounds according to the invention.
According to the invention, the compounds of Formula (1) are prepared by converting compounds of Formula (1), wherein R2 or R3 or R2 and R3 are xe2x80x94Oxe2x80x94R7, into the compounds of the invention by removal of R7, wherein R7 is a substituent suitable as a leaving group, such as, for example, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulfonyl groups, and complexing agents, such as, for example, compounds of boric acid, phosphoric acid and covalently or coordinatively bonded metals, such as zinc, aluminium or copper.
Particularly suitable reactions for the removal of R7 are hydrolyses using suitable bases, such as, for example, sodium hydroxide solution, potassium hydroxide solution or sodium carbonate or potassium carbonate.
These hydrolyses are suitably used when R7 is an acyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl, silyl or sulfonyl residue, and a complexing agent, such as, for example, compounds of boric acid, phosphoric acid and coordinatively bonded metals, such as zinc, aluminium or copper. Particularly suitable reactions for preparing the compounds of the invention for the removal of R7 from the compounds in which R7 is an alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl residue, are ether cleavages, for example by means of hydrobromic acid, hydrochloric acid, hydriodic acid, and using activating Lewis acids, such as, for example, AlCl3, BF3, BBr3 or LiCl, in each case optionally in the presence of additional activators, such as, for example, ethane-1,2-dithiol or benzyl mercaptan, and ether cleavages by means of hydrogen, at elevated pressure or at normal pressure, in the presence of a suitable catalyst, such as, for example, a palladium or iridium catalyst.
According to the invention, the compounds of Formula (1) can also be prepared by converting the substructure: 
of compounds of Formula (1) by a reaction known per se into other compounds of Formula (1). Particularly suitable conversion reactions with compounds of Formula (1) are, for example, when A is xe2x80x94(Cxe2x95x90O), reductions to result in A being xe2x80x94(CHxe2x80x94OH)xe2x80x94or A being xe2x80x94CH2xe2x80x94, by reducing agents known per se, such as, for example, sodium borohydride, or by hydrogenations, which can optionally also be carried out stereoselectively.
Further suitable conversion reactions are the conversion of compounds in which D and E are oxygen into substances in which only D is oxygen, but E is xe2x80x94(Nxe2x80x94Z)xe2x80x94, where Z has the definition given above.
Exemplary processes show below the preparation of compounds of Formula (1) according to the invention from starting substances of the type described, in which R7 is an alkyl, cycloalkyl, arylalkyl, aryl or heteroaryl residue.